Caspofungin is represented by formula 1 below and has the chemical name 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-pneumocandin B0. Caspofungin is a macrocyclic lipopeptide belonging to the echinocandin family, a new class of antifungal agents that inhibits the biosynthesis of beta (1,3)-D-glucan, an integral component of the fungal cell wall. It is useful in treating systemic fungal infections, especially those caused by Candida, Aspergillus, Histoplasma, Coccidioides and Blastomyces. It has also been found to be useful for the treatment and prevention of infections caused by Pneumocystis carinii which are often found in immunocompromised patients such as those with AIDS.

The compound 1-[(4R,5S)-5-[(2-aminoethyl)amino]-N2-(10,12-dimethyl-1-oxotetradecyl)-4-hydroxy-L-ornithine]-5-[(3R)-3-hydroxy-L-ornithine]-pneumocandin B0 and its pharmaceutically acceptable salts are known under the INN caspofungin (see Merck Index, 13th edition, monograph no. 1899).
Processes for preparing caspofungin are described in U.S. Pat. No. 5,378,804, U.S. Pat. No. 5,514,650, U.S. Pat. No. 5,552,521, US 2009/0291996, US 2008/0319162, and U.S. Pat. No. 5,936,062.
U.S. Pat. No. 5,378,804, issued to Merck & Co., Inc. (Rahway, N.J.), discloses aza cyclohexapeptide compounds as caspofungin and fundamental steps of synthesizing caspofungin.
U.S. Pat. No. 5,514,650 discloses: a process comprising allowing alkylthiol or arylthiol to react with, for example, aminoethylthiol from pneumocandin B0, and oxidizing the reaction product to a sulfone intermediate which is then allowed to react with an amine compound, for example, a diamine compound such as ethylenediamine, in an anhydrous aprotic solvent; and a process of isolating the reaction product by chromatography. However, the disclosed process is uneconomical, because the time of reaction of alkylthiol or arylthiol with pneumocandin B0 is long and several chromatographic processes are required to purify the intermediate and the final product, thus reducing the overall synthesis yield.
U.S. Pat. No. 5,552,521 discloses a process of obtaining aza cyclohexapeptide compounds, for example, caspofungin, by reducing the primary amide functional group of pneumocandin B0 to the corresponding amine group and then allowing the reduced compound to react with thiophenol and then with ethylenediamine. However, the yield of the reduction step was reported to be about 43%, and the pungent odor and strong toxicity of thiophenol during the introduction thereof make it difficult to carry out the process. In addition, the step of reaction with thiophenol has a low yield of not more than 70%, and for this reason, the overall yield of the process is not more than 10%.
US 2009/0291996 discloses a preparation process comprising three synthesis reaction steps of synthesizing caspofugin from pneumocandin B0 and two column chromatographic purification steps, wherein the synthesis reaction steps are carried out based on the literature (Leonard et al., J. Org. Chem. 2007, 72, 2335-2343) that describes the actual preparation process in detail. However, as described therein, the synthesis steps provide caspofungin having a purity of not less than 99.0% at a yield of 21.2%. Thus, when a process for increasing the purity of caspofungin is carried out, the yield of caspofungin will be significantly decreased.
US 2008/0319162 discloses a process of converting an amide functional group to a cyano group which is then reduced to the corresponding amine group through hydrogenation, wherein the process is carried out based on the literature (Journet et al., J. Org. Chem. 1999, 64, 2411-2417) which describes an improved process for reducing the primary amide functional group of pneumocandin B0. However, this preparation process needs to be carried out under strictly anhydrous conditions, because the control of water content during a dehydrogenation reaction that is carried out by cyanuric chloride at −30° C. can greatly affect the reaction efficiency. Also, equipment for separating the compounds at low temperature under reduced pressure is required, and a multi-step chromatographic process is used to purify the intermediates and the final product. For this reason, the overall yield of the process was reported to be not more than 10%.
U.S. Pat. No. 5,936,062 discloses two stereoselective processes that use pneumocandin B0 as a starting material. The first process comprises reducing the primary amide functional group of pneumocandin B0 to the corresponding amine group using phenylboronate as a protecting group and allowing the reduced intermediate to react with phenylthiol and then with ethylenediamine. The second process comprises reducing the primary amide functional group of an intermediate, having an S-aryl moiety at the 5-orn position, to the corresponding amine in the presence of phenylboronate as a protecting group, and then allowing the reduced intermediate to react with, for example, ethylenediamine. The intermediate compound, obtained by crystallizing the reaction product in an acidic condition and then reducing the amide group to an amine group, was reported to have a reaction yield of about 61% (HPLC assay).
Accordingly, it is required to develop an improved process which can prepare caspofungin in an environmentally friendly and economical manner.